Search Results (344)

Brain metastases in hormone receptor-positive metastatic breast cancer remain incompletely characterized at the molecular level. We report isolated central nervous system progression in a 60-year-old woman with hormone receptor-positive breast cancer initially diagnosed at the age of 38 and metastatic recurrence diagnosed at the age of 55. After approximately five years of extracranial disease control with letrozole plus palbociclib, she developed multiple brain metastases, including a large cerebellar lesion requiring surgical resection. Molecular profiling of the resected lesion identified ESR1 Y537S and ERBB2 Y772_A775dup, whereas postoperative plasma circulating tumor DNA analyzed using a sensitive next-generation sequencing assay showed no detectable somatic alteration. Extracranial disease remained in complete metabolic response. This tissue–plasma discordance is compatible with spatial genomic heterogeneity but may also reflect a low circulating tumor fraction, postoperative reduction in tumor burden, and limited release of tumor-derived DNA from CNS lesions into the systemic circulation. This case highlights the limitations of plasma circulating tumor DNA for evaluating CNS-limited progression and supports direct molecular profiling of brain metastases when tissue is available. Full article

Melanoma is an aggressive skin cancer that has the potential to metastasize to the lymph nodes, lungs, liver, and brain. Therefore, the prevention and treatment of this condition are essential for achieving lower incidence rates and improving patient outcomes. Traditional treatment methods like surgery, radiation therapy, and chemotherapy have shown limited efficacy in the treatment of metastatic melanoma, and hence new treatment strategies have been developed. These recently developed treatment options include combining targeted therapies with immunotherapies to reduce drug resistance and improve overall effectiveness in preventing melanoma progression. Moreover, BRAF mutations are found in approximately 40–50% of cutaneous melanomas, and NRAS mutations in 15–25%, making these the two most common oncogenic drivers in the MAPK pathway. While alterations in other genes such as KRAS (~1.7%), HRAS (~1%), and MET (~2–4%) are relatively rare in melanoma, they still remain important to disease biology and are under investigation as potential therapeutic targets. These alterations may contribute to tumor progression, metastasis, and therapeutic resistance, highlighting the importance of continued investigation of targeted strategies in melanoma. This review aims to explore the role of each of these genes in melanoma, discusses their resistance mechanism, and summarizes preclinical and clinical trials involving drug combinations. By integrating current evidence on melanoma-associated genomic alterations with available targeted and immune approaches, this review aims to define molecular and clinical contexts that suggest potential treatment selections for melanoma patients. Full article

Background: The metastatic dissemination of melanoma involves adhesion of circulating tumor cells within organ-specific vascular beds; however, the relative contribution of the endothelial environment versus that of the melanoma-intrinsic molecular state remains unclear. Materials and Methods: We quantified the in vitro adhesion of primary (n = 5) and metastatic (n = 3) melanoma cell lines to human hepatic, brain, and pulmonary endothelial cells under co-culture conditions, and we profiled the expression of 86 adhesion- and extracellular-matrix-related genes in melanoma and endothelial cells. Results: Adhesion was highest for the hepatic endothelium, intermediate for the pulmonary endothelium, and lowest for the brain endothelium. This endothelial preference was conserved in both primary and metastatic melanoma cells, though metastatic cells exhibited higher absolute adhesion. The linear mixed-effect models revealed that the effects of adhesion state on melanoma gene expression were modest and varied by endothelial type, whereas melanoma origin had more widespread and larger effects (mean absolute standardized coefficients of 0.32–0.47 versus 0.60–0.87, respectively). The expression of three genes (SPP1, ITGA11, and MMP2) was associated with melanoma origin in all endothelial types. Spearman’s co-expression analysis revealed endothelial-type-specific gene networks, and within-sample permutation confirmed the non-random coordination in all three endothelial types. Conclusions: Our findings support a model in which endothelial organ specificity contributes to melanoma cell adhesion behavior and associated transcriptional patterns, highlighting the importance of the vascular interface as a biologically active mediator of early metastatic cell–endothelium interactions. Full article

Background: Brain metastasis is associated with poor prognosis in lung adenocarcinoma (LUAD). Anoikis resistance may contribute to tumor cell survival during metastatic dissemination and brain colonization; however, robust biomarkers for prognostic stratification and brain metastasis-associated classification remain limited. This study aimed to investigate anoikis-related molecular features in LUAD brain metastasis and develop a machine learning-based signature for prognostic assessment and exploratory classification of primary and brain-metastatic LUAD samples. Methods: We integrated single-cell and multi-cohort bulk transcriptomic data. Single-cell analysis was performed to characterize anoikis-related cellular states and intercellular communication in primary and brain-metastatic LUAD samples. In the bulk transcriptomic analysis, TCGA-LUAD was used for prognostic feature selection and risk-model construction, and GSE26939 was used for external prognostic validation. The classification performance of the fixed signature for distinguishing primary LUAD from brain-metastatic LUAD samples was further evaluated in GSE161116 and GSE271259. Immune microenvironment features were assessed, and an LLM-assisted exploratory drug-screening strategy combined with molecular docking was used to prioritize candidate compounds. Results: Single-cell analysis suggested that metastatic epithelial cells exhibited enhanced anoikis-related activity, accompanied by macrophage-associated SPP1-CD44 and MIF-(CD74+CXCR4) communication patterns. Machine learning-based feature selection identified an eight-gene signature consisting of BIRC3, CCL20, CLEC7A, CTSL, GOLM1, ICAM3, MTUS1, and SERPINH1. The signature showed prognostic value in TCGA-LUAD and GSE26939 and demonstrated exploratory classification performance in distinguishing primary LUAD from brain-metastatic LUAD samples. High-risk patients exhibited immune microenvironment alterations and enrichment of tumor progression-related pathways. LLM-assisted compound prioritization and molecular docking highlighted resveratrol and SB431542 as hypothesis-generating candidates with predicted interactions with core targets. Conclusions: This study identified an anoikis-related eight-gene signature for LUAD prognostic stratification and exploratory brain metastasis-associated classification. The findings suggest the potential involvement of anoikis-related tumor–microenvironment interactions in LUAD brain metastasis and provide candidate genes and compounds for further experimental validation. Full article

Background and Clinical Significance: Thyroid cancer is increasing, particularly the differentiated type, with decreasing incidence of the anaplastic type. Anaplastic thyroid carcinoma (ATC) is a rare, aggressive, and often lethal form. It frequently presents with metastatic disease, regional and systemic, with common distant metastasis to the lung, bone, brain, and adrenal, and rarely to other places; Case presentation: A 74-year-old Arab male presented with symptomatic anemia and melena and was admitted for investigation of the cause. The patient was found to have a large retrosternal goiter and gastric tumor. CT scan showed a pedunculated, nonobstructive mass, suggestive of a GIST or leiomyoma. The neck mass presented with compressive symptoms. He underwent a combined neck and abdominal surgical resection based on a multidisciplinary team decision, as prior biopsies were not conclusive. The final pathology report identified similar tumors in the two specimens and suggested an anaplastic thyroid carcinoma as the primary tumor with metastasis to the stomach. Furthermore, the workup, including a PET scan 2 weeks post-surgery, revealed widespread metastases in the bone, lung, and liver, and the treatment was palliative. He was followed up in the outpatient clinic for 4 and a half months post-operatively. The patient developed sepsis and cardiopulmonary arrest and died; Conclusions: ATC can metastasize to many places in the body, including the stomach (as shown in our case), which can cause significant upper gastrointestinal bleeding and anemia. Metastatic ATC carries a poor prognosis; thus, physicians need to keep a high index of suspicion in approaching similar cases. A multidisciplinary approach for the management is of utmost importance for appropriate treatment. This disease’s pathology, behavior, and targeted new treatment modalities must be explored further. Full article

Background/Objectives: Diagnosing hemangioblastomas using magnetic resonance imaging (MRI) is challenging, especially when the tumors appear as solid posterior fossa masses. This study aimed to evaluate the diagnostic performance of perfusion MRI and identify the most useful quantitative features for differentiating hemangioblastomas from other posterior fossa tumors. Methods: Forty-five posterior fossa tumors were analyzed, including 18 hemangioblastomas (HB group) and 27 non-hemangioblastoma tumors (NHB group; 8 metastatic brain tumors, 6 pilocytic astrocytomas, 5 malignant lymphomas, 4 glioblastomas, 2 medulloblastomas, and 2 other tumors). All patients underwent 3.0-T MRI. Arterial spin labeling (ASL) was used to calculate the relative tumor blood flow normalized to the contralateral gray matter. Dynamic susceptibility contrast (DSC) imaging was used to obtain regional cerebral blood flow, regional and corrected cerebral blood volume (CBV), and permeability index (K2) values. Regions of interest (ROIs) were placed within the contrast-enhancing areas. Results: The relative ASL values and corrected CBV were significantly higher in hemangioblastomas than in other tumors (p < 0.001). Relative ASL showed the highest diagnostic performance (sensitivity, 100%; specificity, 93.3%). Conclusions: Non-contrast ASL showed strong diagnostic performance for identifying posterior fossa hemangioblastomas and may serve as a practical alternative to contrast-enhanced DSC, although ROI placement can be challenging in very small mural nodules. Full article

Background: Oligometastatic non-small cell lung cancer (OMD NSCLC) represents a distinct clinical state with limited metastatic spread, where local ablative therapies (LAT) combined with systemic treatment may improve outcomes. Accurate staging and prognostic assessment are critical, with ¹⁸F-FDG PET/CT emerging as a valuable tool for detecting metabolically active tumor burden. Results: We retrospectively analyzed 38 patients with synchronous OMD NSCLC who received radiotherapy. All patients underwent ¹⁸F-PET/CT and brain imaging for staging. Semi-quantitative ¹⁸F-PET/CT parameters, including metabolic tumor volume (MTV) and total lesion glycolysis (TLG) of primary tumor and metastatic lesions, were measured and associated with progression-free survival (PFS) and overall survival (OS) using Cox proportional hazard models. The median PFS and OS were 8.28 and 21.62 months, respectively. Higher MTV and TLG values of metastases were significantly associated with shorter PFS and OS (p < 0.01). In multivariable analysis, TLG of metastases above the median remained an independent predictor of worse PFS (HR = 2.78, p = 0.031) and OS (HR = 3.12, p = 0.024), alongside clinical factors such as ECOG performance status 2 and having multiple metastases. The metabolic parameters of the primary tumor did not predict survival outcomes. Conclusions:¹⁸F-PET/CT-derived metabolic parameters, particularly the TLG of metastatic lesions, may provide significant prognostic information in oligometastatic NSCLC beyond clinical variables. These findings may support the integration of ¹⁸F-PET/CT metrics for future trials involving patients treated with LAT in oligometastatic NSCLC. Full article

Background: Brain metastases are the most common intracranial tumors in adults and are traditionally considered well-demarcated lesions amenable to complete surgical resection. Nonetheless, increasing histopathological evidence demonstrates that metastatic cells may infiltrate beyond the contrast-enhancing margin into surrounding brain parenchyma, challenging the reliability of conventional imaging for defining true tumor boundaries. Confocal laser endomicroscopy (CLE) using Sodium Fluorescein (SF) has emerged as a novel intraoperative imaging modality capable of providing real-time, high-resolution optical biopsies, potentially improving margin assessment during metastasis surgery. Methods: A systematic literature search was performed according to PRISMA guidelines across PubMed, Embase, Scopus, Cochrane Library, and Google Scholar up to 3 March 2026. Studies evaluating intraoperative CLE with SF in adult patients with brain metastases were included. Data regarding study design, patient population, CLE system, imaging characteristics, and diagnostic performance were extracted. Risk of bias was assessed using the QUADAS-2 tool. Results: Ten studies met the inclusion criteria for qualitative synthesis, comprising over 650 patients; however, most studies included heterogeneous intracranial tumor populations, with only a subset specifically involving brain metastases. CLE enabled real-time visualization of tumor microarchitecture and demonstrated high sensitivity for tumor detection, frequently exceeding 90% in prospective studies. Specificity varied across studies, reflecting challenges in distinguishing tumor infiltration from reactive tissue at the tumor–brain interface. The MetInfilt trial highlighted that infiltrative growth patterns are common in brain metastases and can be visualized intraoperatively using CLE. Additional studies demonstrated that fluorescein-based CLE allows differentiation of tumor zones and may facilitate targeted margin assessment; however, evidence demonstrating improvement in clinically meaningful outcomes such as extent of resection, local recurrence, progression-free survival, or overall survival remains limited. Conclusions: Confocal laser endomicroscopy using SF represents a promising intraoperative adjunct for assessing tumor margins in brain metastasis surgery. By enabling real-time microscopic visualization of the metastasis–brain interface, CLE may support a more biologically informed surgical strategy. Full article

Short-term mortality following the last dose of immune checkpoint inhibitors (ICIs) is an increasingly recognized real-world outcome measure, yet its clinical predictors remain poorly characterized. This multicenter retrospective study included 458 consecutive patients with advanced melanoma, non-small cell lung cancer, or renal cell carcinoma who received ICIs at four tertiary centers in Turkey between 2018 and 2023. The primary endpoint was 30-day mortality after the final ICI dose. Among 458 patients, 71 (15.5%) died within 30 days. Multivariable logistic regression identified ECOG performance status ≥ 2, number of metastatic sites ≥ 3, and log-transformed C-reactive protein-to-albumin ratio (log-CAR) as independent predictors of 30-day mortality in Model 1 (AUC 0.954), while ECOG PS ≥ 2, brain metastasis, metastatic sites ≥ 3, and log-NLR were independent predictors in Model 2 (AUC 0.912). In the lung cancer subgroup, log-CAR and NLR remained independent predictors while ECOG PS did not. Patients who died within 30 days had significantly shorter progression-free survival (1.18 vs. 4.63 months) and overall survival (2.30 vs. 14.39 months) compared with survivors. These findings suggest that routine assessment of inflammatory and nutritional biomarkers alongside tumor burden parameters may help identify patients at high risk of early mortality and inform the timing of supportive care in ICI-treated populations. Full article

Background: Breast cancer with isolated bone metastases at initial diagnosis represents a clinically distinct metastatic phenotype, often associated with more indolent biology and relatively favorable outcomes compared with visceral metastatic disease. The survival impact of resecting the intact primary breast tumor in de novo metastatic breast cancer remains controversial. In this study, we evaluated the association between primary breast surgery and overall survival (OS), defined as the time from diagnosis to death attributable to breast cancer, in patients presenting with isolated bone metastatic breast cancer. Methods: We performed a retrospective population-based cohort study using the Surveillance, Epidemiology, and End Results (SEER) database. Because the SEER variable for bone metastasis at diagnosis is available from 2010 onward and HER2-defined subtype information is available in the modern SEER era, the effective study period was defined as 2010–2021 rather than the full 2000–2021 SEER release period. Patients with breast cancer and isolated bone metastases at presentation, without evidence of lung, liver, brain, or other distant metastatic sites at diagnosis, were included. Demographic and clinicopathological variables, including age, sex, race, biologic subtype, histology, chemotherapy, radiotherapy, and primary breast surgery, were analyzed. Overall survival (OS), defined as the time from diagnosis to death attributable to breast cancer, was estimated using Kaplan–Meier methods and compared using the log-rank test. Independent prognostic factors were evaluated using multivariable Cox proportional hazards modeling. Results: A total of 6500 eligible patients were identified. Surgery of the primary breast tumor was performed in 1513 (23.3%) patients, and 62.8% received chemotherapy. Five-year overall survival (OS) was significantly higher among patients who underwent surgery than among those who did not undergo surgery (59.5% vs. 38.6%; p < 0.001). In multivariable analysis, primary breast surgery remained independently associated with improved OS (hazard ratio [HR] 0.54, 95% CI 0.48–0.62; p < 0.001). Age, histology, chemotherapy, radiotherapy, and biologic subtype were also associated with prognosis. Sex was not significant in the unadjusted analysis (p = 0.188), and the multivariable sex finding was interpreted cautiously because only 96 men were included. Conclusions: In this population-based cohort of patients with de novo breast cancer and isolated bone metastases, primary breast surgery was associated with improved survival among selected patients. However, this association should not be interpreted as causal, given the inherent limitations of observational registry data, including treatment selection, potential immortal-time bias, unmeasured metastatic burden, performance status, systemic therapy type and response, and local symptom burden, which are not fully captured in SEER. These findings support careful multidisciplinary consideration of local therapy in selected patients, while emphasizing the need for confirmation in prospectively designed studies. Full article

Background and Objectives: The systemic inflammatory response is important in cancer prognosis and progression. The inflammatory burden index (IBI) provides information about both inflammation and the immune response. Urothelial carcinomas are immunogenic; therefore, it has been suggested that inflammatory indices may predict disease prognosis. The aim of this study was to investigate the effects of systemic inflammatory indices, particularly the inflammatory burden index, on disease progression and overall survival in patients with metastatic urothelial cancer (affecting the bladder and upper urinary system) before first-line treatment and to demonstrate their prognostic importance. Materials and Methods: Within the scope of the study, the medical records of 130 patients who received systemic treatment for metastatic urothelial carcinoma at the medical oncology clinic were retrospectively reviewed. Receiver operating characteristic (ROC) curve analysis was performed to determine the optimal threshold values for IBI. Survival rates were calculated using the Kaplan–Meier method, and survival differences between groups were compared with the log-rank test. Univariate and multivariate analyses were performed using the Cox proportional hazards regression model to evaluate prognostic factors. Results: A total of 130 patients were included in the study. The median age was 64.9 years (IQR: 57.2–70.5). The primary tumor location was the bladder in 84.6% of patients, while the remaining 15.4% originated from the ureter and renal pelvis. In first-line systemic treatment, patients received a median of 4 cycles (IQR: 3–6). The median number of total treatment lines administered for metastatic disease was 1 (IQR: 1–2). In progression-free survival (PFS) analyses, the median PFS was 9.20 (95% CI 6.55–11.85) months in the IBI-low group (n = 47) and 5.82 (95% CI 4.56–7.07) months in the IBI-high group (n = 83) (p < 0.001). The median OS was calculated to be 18.96 (95% CI 16.61–21.30) months in the IBI-low group (n = 47), while it was found to be 9.50 (95% CI 7.70–11.29) months in the IBI-high group (n = 83) (p < 0.001). In multivariate analysis, high IBI and the presence of brain metastasis were found to be associated with the risk of progression. In terms of overall survival, the presence of brain metastasis, the presence of visceral metastasis, ECOG PS status, receipt of maintenance therapy, LMR, and the IBI score showed statistically significant prognostic effects. Conclusions: In metastatic urothelial carcinoma, the IBI was identified as an independent prognostic factor associated with progression-free and overall survival. These findings suggest that the IBI may have potential utility as a prognostic biomarker; however, larger, multicenter, and prospective studies are required to further validate its clinical applicability. Full article

Intraoperative fluorescence-guided surgery is an important adjunct to brain tumor resection. However, fluorescent probe performance varies across molecularly and histopathologically distinct entities, including IDH-wildtype glioblastoma, metastatic brain tumors (MBTs), and primary central nervous system lymphoma (PCNSL), and the mechanisms underlying this variability remain poorly understood. We propose a mechanistic framework integrating biomechanical constraints, molecular barrier heterogeneity, and probe-specific pharmacokinetics to explain cross-tumor differences in fluorescence signal. Probe performance is conceptualized through three sequential bottlenecks: extravasation (blood–brain barrier/blood–tumor barrier permeability and transcytosis), interstitial penetration (extracellular matrix density and hydraulic resistance), and retention/clearance (efflux transporters and metabolic processing). An overlying optical layer, including tissue absorption, scattering, and autofluorescence, further modulates the detected signal. Tumor-specific molecular heterogeneity critically shapes these processes. In IDH-wildtype glioblastoma and legacy high-grade glioma cohorts, heterogeneous expression of ATP-binding cassette transporters has been associated with reduced intracellular accumulation of protoporphyrin IX after 5-aminolevulinic acid administration and may contribute to false-negative fluorescence in selected tumor regions. In MBTs, stage-dependent blood–tumor barrier integrity and vascular programs influence probe delivery, whereas in PCNSL, corticosteroid-sensitive restoration of endothelial barrier function may compromise the performance of leakage-dependent tracers. Together, this framework highlights how tumor biology, barrier function, and probe pharmacology jointly shape fluorescence contrast. Rational probe selection informed by tumor-specific transport and barrier constraints may improve intraoperative visualization of brain tumors and optimize surgical decision-making. Full article

Background and Objectives: Renal cell carcinoma (RCC) exhibits heterogeneous and sometimes unpredictable metastatic behavior, involving both common and uncommon anatomic sites. Institutional analyses of histopathologically confirmed metastatic RCC may improve diagnostic recognition and clinical awareness. This study aimed to characterize the metastatic distribution and histopathologic features of RCC diagnosed in a single tertiary center over a five-year period. Materials and Methods: A retrospective review of the pathology database of the Department of Pathology, “Pius Brînzeu” Emergency County Hospital, Timișoara, was performed to identify all histologically confirmed cases of metastatic RCC diagnosed between January 2020 and December 2024. Case identification was based on pathology reports of metastatic lesions. In a subset of cases, corresponding pathology reports of the primary renal tumor were available and reviewed. Histopathological data collected included WHO/ISUP grade, tumor necrosis, sarcomatoid and/or rhabdoid differentiation, vascular invasion, surgical margin status, tumor size, and pathological T stage (pT). Exploratory analyses were performed to assess associations between metastatic site and selected histopathological features. Results: Thirty-two cases of metastatic RCC were identified, all demonstrating clear cell morphology. The mean patient age was 62.9 years, with a marked male predominance. Among cases with available primary tumor data, high WHO/ISUP grade and adverse histopathologic features were frequently observed. The most common metastatic sites in our institution were the brain and bone, followed by the adrenal gland, lymph nodes, and liver. Less frequent metastatic involvement included the pancreas, testis, vagina, skin, and peritoneum. Exploratory analyses did not demonstrate statistically significant associations between metastatic site and tumor grade, necrosis, or sarcomatoid/rhabdoid differentiation; however, descriptive trends were observed, including the association of brain metastases with high-grade tumors and the high prevalence of tumor necrosis across metastatic sites. Conclusions: This pathology-based retrospective series highlights the broad metastatic spectrum of RCC, including both typical and rare anatomic sites. The predominance of clear cell morphology and the frequent association with adverse histopathologic features support the link between aggressive tumor biology and metastatic disease. Although no statistically significant associations were identified, the observed patterns suggest potential relationships between metastatic distribution and tumor characteristics, warranting further investigation in larger studies. Full article

Oncogenic driver mutations in non-small cell lung cancer (NSCLC) activate defined signaling pathways that sustain tumor growth and influence the immune landscape. Yet, how coordinated interactions among diverse cell populations within the tumor immune microenvironment (TIME) contribute to this process remains largely unresolved. To address this, we profiled approximately 200,000 single cells from 45 treatment-naïve NSCLC patients representing seven major driver mutations. This analysis uncovered five multicellular modules (CM1–5) with distinct functional properties, each linked to specific malignant regulatory programs. Among them, CM2 and CM5 exhibited pronounced invasive features and were associated with unfavorable clinical outcomes. CM2 was predominantly observed in EGFR- and MET-driven brain metastases and was defined by strong crosstalk between astrocytes and myofibroblasts. Factors such as SPP1, PTN, and PSAP, together with metabolic alterations, contributed to a microenvironment supportive of metastatic colonization in the brain. By contrast, CM5 was enriched in ROS1-, KRAS-, and EGFR-mutant tumors and consisted of diverse myeloid and endothelial subsets characterized by immunosuppressive and pro-angiogenic signaling, including MIF, GALECTIN, and RETN, collectively facilitating immune escape and vascular remodeling. We further constructed and validated a driver mutation-specific prognostic signature (DMSP.sig) model integrating receptor–ligand interactions and core transcription factors, which effectively stratified patient survival. Leveraging this model, we also identified potential therapeutic candidates linked to these prognostic features, highlighting opportunities for clinical intervention. In summary, our study delineates how oncogenic drivers give rise to distinct TIME architectures, providing a framework for prognostic assessment and precision immunotherapy in high-risk NSCLC. Full article

Breast cancer brain metastasis (BCBM) affects up to 30% of patients with metastatic disease and carries a median survival of only 4–18 months. Emerging evidence reveals that BCBM cells are not passive survivors, but active participants that hijack core neurotransmitter networks, GABA (gamma-aminobutyric acid) and glutamate, to fuel their growth. BCBM, particularly triple-negative breast cancer (TNBC), frequently switch to a GABAergic mode utilizing brain-derived GABA as an oncometabolite. In parallel, BCBM cells can also form direct synapses with neurons, tapping into excitatory input through glutamatergic receptors to drive tumor cell proliferation and survival. Concurrently, reprogrammed astrocytes establish gap junctions, secrete growth factors, and provide metabolic support. Together, tumor cells, neurons, and astrocytes form a pathological partnership locked in feedback loops sustaining metastatic progression. This review focuses on the unique mechanisms employed by distinct breast cancer subtypes and maps the metastatic progression from pre-metastatic to mature brain metastatic niche formation of BCBM. We highlight opportunities to repurpose neurological drugs to disrupt these communication axes. Full article